Potent trophic effects of aluminum on bone have recently been identified in the investigator's laboratory. In this regard, aluminum substantially increases bone density and volume in normal beagles due to an uncoupling of bone remodeling and de novo bone histogenesis within the marrow cavity. These pharmacologic skeletal effects are unprecedented and may provide a means whereby new three-dimensional trabecular structures can be generated. The long-term objective of this proposal is to understand the mechanism(s) of this unique osteoinductive action. In pursuit of this goal, the effect of aluminum to stimulate bone formation will be further characterized in vivo and the potential to induce mitogenesis in cell culture systems will be explored. The specific aims of the animal studies are to confirm the time course of aluminum-induced osteogenesis in trabecular bone and to examine the effects of aluminum on cortical bone; to determine if the resultant woven bone remodels, persists after the cessation of aluminum treatment, and imparts structural integrity to bone; and to identify whether this agent can restore bone in osteopenic models. The in vitro studies will: (1) determine if this osteoinductive action is indirectly mediated through the release of paracrine factors from monocytes; and (2) test for potential direct actions of aluminum, explore the interrelationships between aluminum and specific endogenous growth factors and/or exogenous mitogen, and determine the influence of cell differentiation on aluminum action using cell culture systems of osteoblasts and mesenchymal precursors. Information obtained from these studies will likely lead to a better understanding of a novel agent(s) with osteogenic potential and may be useful in designing effective therapy for currently refractory osteopenic disorders.